Management and interpretation of heterogeneous observational data: using insulin-like growth factor-I data from the NordiNet® International Outcome Study

Growth Horm IGF Res. 2015 Feb;25(1):41-6. doi: 10.1016/j.ghir.2014.12.001. Epub 2014 Dec 9.

Abstract

Objective: The NordiNet® International Outcome Study (IOS), a large-scale, non-interventional, multi-centre, real-world study of Norditropin® treatment, registers insulin-like growth factor-I (IGF-I) values, as measured by different assays. This paper considers the potential biases introduced by using a single IGF-I reference data set in analysing NordiNet® IOS data.

Design: To evaluate possible biases from different IGF-I assays used across NordiNet® IOS, a mixed-effect linear model was fitted to IGF-I data (analyses on log-transformed data). Pre-growth hormone treatment (pre-GHT) IGF-I values were assumed to depend on diagnosis, sex and age. During GHT, a treatment-effect dependent on these factors was added. Differences between assays were assumed multiplicative on the original scale. Individual measurements were scaled to a common level (Nichols Advantage) giving adjusted IGF-I standard deviation score (SDS) values.

Results: In total, 49 495 IGF-I measurements were available from 9481 paediatric patients. Mixed-effect linear modelling showed a systematic difference between IGF-I levels measured by different assays. Differences were minimised when assessing change in IGF-I SDS from the start of GHT to 1-year follow-up. This applied to values adjusted for actual-assay used and for unadjusted delta IGF-I SDS values. Largest differences between unadjusted change in IGF-I SDS values were: for growth hormone deficiency 0.1 (girls) and 0.3 (boys); for small-for-gestational age 0.1; and for Turner syndrome 0.2. Similar magnitude differences were seen for data with unknown assay.

Conclusions: Analysis and modelling suggest the current approach to IGF-I data collection and analyses in the NordiNet® IOS is sound: in a large cohort without assay-used information, potential bias is minimised by analysing changes in IGF-I SDS.

Keywords: Assay; Growth hormone; Growth hormone therapy; IGF-I; Norditropin®; Pharmacoepidemiology.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Child
  • Child, Preschool
  • Female
  • Growth Disorders / drug therapy*
  • Growth Disorders / etiology
  • Growth Disorders / metabolism
  • Human Growth Hormone / therapeutic use*
  • Humans
  • Hypopituitarism / complications
  • Hypopituitarism / drug therapy*
  • Hypopituitarism / metabolism
  • Immunoassay / standards
  • Infant, Newborn
  • Infant, Small for Gestational Age
  • Insulin-Like Growth Factor I / analysis
  • Insulin-Like Growth Factor I / metabolism*
  • Linear Models
  • Male
  • Outcome Assessment, Health Care
  • Reference Standards
  • Turner Syndrome / complications
  • Turner Syndrome / drug therapy*
  • Turner Syndrome / metabolism

Substances

  • IGF1 protein, human
  • Human Growth Hormone
  • Insulin-Like Growth Factor I